Chronic urticaria and autoimmunity: Associations found in a large population study

Ronit Conno-Cohen, MD,a,b Gabriel Chodick, PhD,b,c Varda Shalev, MD,b,c Moshe Leshno, MD, PhD,b Oded Kimhi, MD,d and Arnon Goldberg, MDa,b Kfar Saba and Tel Aviv, Israel Background: Chronic urticaria (CU) is a common disease in which most cases were considered to be idiopathic. Recent evidence indicates that at least a subset of cases of chronic idiopathic urticaria are autoimmune in origin. Objective: We aimed to characterize the association between CU, autoimmune diseases, and autoimmune/inammatory serologic markers in a large unselected population. Methods: Data on 12,778 patients given a diagnosis of CU by either allergy or dermatology specialists during 17 years in a large health maintenance organization in Israel were collected. For each patient, we collected information on diagnosis of major, well-dened autoimmune diseases and autoimmunityand inammatory-related serologic markers. Similar data were collected for a control group comprised of 10,714 patients who visited dermatologists, family physicians, or allergy specialists and had no indication of CU. Results: Having CU was associated with an increased odds ratio for hypothyroidism, hyperthyroidism, and antithyroid antibodies. Female patients with CU had a signicantly higher incidence of rheumatoid arthritis, Sjgren syndrome, celiac o disease, type I diabetes mellitus, and systemic lupus erythematosus, mostly diagnosed during the 10 years after the diagnosis of CU. High mean platelet volume, positive rheumatoid factor, and antinuclear antibodies were all signicantly more prevalent in patients with CU. Conclusions: A strong association was found between CU and major autoimmune diseases. A common pathogenic mechanism is implied by the high prevalence of autoantibodies and the existence of a chronic inammatory process expressed by the high mean platelet volume. These ndings have implications for the diagnosis, management, and prognosis of patients with CU. (J Allergy Clin Immunol 2012;129:1307-13.) Key words: Chronic urticaria, autoimmunity, hypothyroidism, hyperthyroidism, rheumatoid arthritis, Sjgren syndrome, celiac diso ease, type I diabetes mellitus, systemic lupus erythematosus, mean platelet volume

Abbreviations used ASST: Autologous serum skin test CIU: Chronic idiopathic urticaria CU: Chronic urticaria ICD-9-CM: International Classication of Diseasesninth revision Clinical Modication MHS: Maccabi Healthcare Services MPV: Mean platelet volume OR: Odds ratio RA: Rheumatoid arthritis SLE: Systemic lupus erythematosus

Chronic urticaria (CU) is dened as having recurrent urticarial lesions for more than 6 weeks, with symptoms present at least 3
From athe Allergy and Clinical Immunology Unit and dthe Department of Medicine, Meir Medical Center, Kfar Saba; bSackler Faculty of Medicine, Tel Aviv University; and c the Medical Division, Maccabi Healthcare Services, Tel Aviv. Disclosure of potential conict of interest: The authors declare that they have no relevant conicts of interest. Received for publication August 28, 2011; revised January 2, 2012; accepted for publication January 9, 2012. Available online February 14, 2012. Corresponding author: Ronit Conno-Cohen, MD, Allergy and Clinical Immunology Unit, Meir Medical Center, Kfar Saba 44281, Israel. E-mail: ronitco@clalit.org.il. 0091-6749/$36.00 2012 American Academy of Allergy, Asthma & Immunology doi:10.1016/j.jaci.2012.01.043

times weekly.1-3 When the cause is not detected after intensive clinical and laboratory investigation, it is dened as idiopathic. In the past few years, autoimmune mechanisms have been proposed as responsible for the development of some of the cases of chronic idiopathic urticaria (CIU). The suspected autoimmune background was supported by the observation that intradermal injection of autologous serum elicited immediate wheal-and-are responses in 60% of patients with CIU.1 Subsequent work demonstrated the presence of the IgG autoantibodies anti-IgE and IgG anti-FcRI in sera from 45% to 55% of patients with CIU. In view of these data, it was suggested that a substantial number of patients with CIU have an autoimmune process induced by the anti-IgE and anti-FcRI antibodies targeted at basophils and mast cells.2 Because many autoimmune diseases overlap, it was suggested that CU might be related to other autoimmune processes. Thyroid disease is the most frequently investigated disease in association with CIU. Leznoff and Sussman3 reported a relation between thyroid autoimmunity and CIU. They proposed a syndrome of autoimmune thyroid disease, CU, and angioedema, with thyroid autoantibodies identied in 15% of patients.3 However, in other reports the incidence of thyroid autoantibodies in patients with CU ranges from 6.5%4 to 57%.5 Subsequently, several studies approached this issue, but many consisted of small, not well-controlled series.6 Limited data exist regarding other autoimmune processes related to CIU. Most of these reports include small series of patients or case reports. For example, celiac disease was described by Meneghetti et al7 in 3 of 32 children and adolescents with CU, and Bachert et al8 reported Raynaud phenomenon with anticentromere antibodies in 5 of 257 patients with CU. Only 1 survey investigated serologic markers of autoimmunity in patients with CU. It demonstrated that antibodies to thyroid peroxidase and rheumatoid factor were increased in patients with urticaria, but other markers of autoimmunity were not found.9 The connections between CIU, thyroid disease, and other autoimmune diseases or serologic markers have major implications for understanding the pathophysiology of the disease. The autoimmune diseases are a heterogynous group. If we are to
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view CIU as an autoimmune disease, the association with other autoimmune diseases must be claried. This is the rst step in establishing possible causality, common cause, or other more intricate associations. Moreover, an autoimmune background might inuence the workup and follow-up of these patients, as well as their therapeutic options and prognosis. In this study we evaluated the associations between CU, major autoimmune diseases, and serologic markers in a large group of unselected patients.

METHODS Data source

This study was carried out at Maccabi Healthcare Services (MHS), a 2-million-enrollee health maintenance organization in Israel. The automated health plan databases contain information on all diagnoses and laboratory examinations that are performed at a single laboratory in central Israel. This database was used to obtain individual-level information on diagnoses and laboratory results by means of cross-linkage using a unique patient identier. The study was approved by the MHS Institutional Review Board.

RESULTS During the study period, 12,778 patients were given diagnoses of CU. Of these, 8,472 (66.3%) were women, and 4,306 (33.6%) were men, with an average age of 45.3 6 18.5 years. The control group comprised 10,714 patients, 9,188 (85.7%) women and 1,526 (14.3%) men, with an average age of 44.2 6 14.2 years. According to the preliminary results, the majority of patients with CU were women. Consequently, the forthcoming analyses were stratied by sex. Table I presents the odds of having autoimmune disease in patients with CU compared with control subjects. Thyroid diseases and CU Thyroid diseases were the most common accompanying diseases in patients with CU, 9.8% (1257) had hypothyroidism compared with 0.6% (67) in the control group (P < .0005). In patients with CU and control subjects, hypothyroidism was signicantly more common in women. The odds of having hypothyroidism was 23.07 times greater for female patients with CU compared with the odds in the control group (95% CI, 17.80-29.91; P < .0005). On the other hand, the OR of having hypothyroidism was 7.57 when comparing male patients with CU with those in the control group (95% CI, 3.33-17.21; P < .0005). In 80.9% of patients with CU with hypothyroidism, the condition was diagnosed within 10 years of the diagnosis of CU. Hypothyroidism was diagnosed shortly after the diagnosis of CU (within the rst 6 months) in only 3.6% of patients with CU. Hyperthyroidism was less common in both groups, yet it was signicantly more prevalent in the CU group than in the control group (2.6% and 0.09%, respectively; P <.0005). The odds of having hyperthyroidism was 34.98 times greater for female patients with CU compared with the odds in the control group (95% CI, 18.00-67.99; P < .0005). In the male population the OR of having hyperthyroidism was 19.73 in the patients with CU compared with the control group (95% CI, 2.72-142.69; P < .0005). Hyperthyroidism was diagnosed before CU in only 17.6% of the patients. In most patients with CU (82.4%), hyperthyroidism was diagnosed within 10 years of the diagnosis of CU and in only 4.3% of these within the rst 6 months. Accompanying the thyroid diseases, antithyroid antibodies were found in 306 patients with CU with hypothyroidism: antithyroid peroxidase antibodies were found signicantly more in women and men with CU than in control subjects (6% vs 0.3% for women and 2.1% vs 0.5% for men, respectively; P < .0005). Antithyroglobulin antibodies were positive in 1.4% (n 5 117) of the women with CU compared with 0.1% (n 5 1) of female control subjects (P < .0005) and in 0.5% (n 5 21) of the men with CU compared with 0.04% (n 5 4) in men of the control group (P < .0005). Of the 11,514 euthyroid patients in the CU group, 74 had antithyroglobulin antibodies, and 312 had antithyroperoxidase antibodies. In the euthyroid control group 6 had antithyroperoxidase antibodies, and 1 had antithyroglobulin antibodies. These differences were signicant (P < .0001, OR 5 17.375 for antithyroperoxidase; P < .0001, OR 5 24.244 for antithyroglobulin antibodies). Other autoimmune diseases and CU Other autoimmune diseases were signicantly more common in patients with CU: the odds of having RA was 13.25 for the group of all patients with CU compared with the control group

Study population
Using an automated search on the MHS central database, we collected data on all patients given a diagnosis of CU by either allergy and clinical immunology or dermatology specialists between January 1, 1993, and March 1, 2010, using the International Classication of Diseasesninth revisionClinical Modication (ICD-9-CM). All other types of urticaria, including physical urticaria, cholinergic urticaria, dermographism, and urticaria without specication of chronic, have distinct ICD-9-CM classications and were not included. The control subjects were patients who visited dermatologists, family physicians, or allergy specialists during this period and were not given a diagnosis of CU or any other specic disease but were given diagnoses with the ICD-9-CM patient under observation diagnosis. Control subjects were frequency matched with cases by age and sex. For each patient, we collected information on diagnostic history of the following conditions: hypothyroidism, hyperthyroidism, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), celiac disease, type 1 diabetes mellitus, and Sjgren syndrome. The rst registrao tion date for each diagnosis was collected as well. The information regarding the following laboratory tests was also collected: antithyroid peroxidase antibodies, antithyroglobulin antibodies, antinuclear antibodies, rheumatoid factor, antidouble-stranded DNA antibodies, anticardiolipin antibodies, antitransglutaminase IgA antibodies, antiparietal cell antibodies, and mean platelet volume (MPV). Studies for antibodies to FcRI or IgE were not collected because they are not available in Israel for routine clinical work. For each patient, we calculated the number of laboratory tests performed and the proportion of abnormal test results.

Statistical analysis
All analyses were performed separately for men and women. All data were summarized and displayed as the number of patients plus the percentage in each group for categorical variables and as means 6 SDs for continuous variables. Categorical variables were compared between groups by using the x2 test. To further estimate differences between each autoimmune risk factor and CU, we calculated odds ratios (ORs) and 95% CIs. Logistic regression was used to predict the association between autoimmune diseases and MPVamong patients with CU. When using this method, the results were highly signicant, and Bonferroni correction (with a signicant value of (1 2 [1 2 0.05])(1/k), k is the number of comparisons), would not modify the results. Thus we decided to present the ORs, as well as the 95% CIs and P values. All analyses were 2-sided, and a P value of less than .05 was considered statistically signicant. All analyses were performed with SPSS 19.0 software (SPSS, Inc, Chicago, Ill).

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TABLE I. Autoimmune diseases in patients with CU and control subjects

Total population (n 5 12,778 patients with CU and 10,714 control subjects) Disease OR 95% CI P value Female subjects (n 5 8,472 patients with CU and 9,188 control subjects) OR 95% CI P value Male subjects (n 5 4,306 patients with CU and 1,526 control subjects) OR 95% CI P value

Hypothyroidism Hyperthyroidism RA Type I diabetes mellitus Sjgren syndrome o Celiac disease SLE

17.338 28.81 13.25 7.703 15.17 26.96 14.59

13.51-22.2 15.40-54.25 7.39-23.76 4.78-12.65 5.54-14.54 6.6-110.17 4.56-46.73

<.0005 <.0005 <.0005 <.0005 <.0005 <.0005 <.0005

23.07 34.98 19.88 12.92 23.30 57.83 26.71

17.80-29.91 18.00-67.99 10.15-38.92 6.53-25.53 7.31-74.20 7.99-418.29 6.49-109.90

<.0005 <.0005 <.0005 <.0005 <.0005 <.0005 <.0005

7.57 19.73 2.96 2.34 2.83 3.90 1.06

3.33-17.21 2.72-142.69 0.89-9.83 1.15-4.73 0.35-22.71 0.50-30.27 0.11-10.22

<.0005 <.0005 .06 .01 .30 .16 .96

TABLE II. Timing of rst diagnosis of autoimmune disease in relation to diagnosis of CU

Before diagnosis of CU (%) Disease Women Men Total Women After diagnosis of CU (%) Men Total

Hypothyroidism Hyperthyroidism RA Type I diabetes mellitus Sjgren syndrome o Celiac disease SLE

218/1132 49/281 28/162 18/106 13/64 6/53 8/49

(19.3) (17.4) (17.3) (17.0) (20.3) (11.3) (16.3)

22/125 10/55 4/25 7/59 3/8 5/11 0

(17.6) (18.2) (16.0) (11.9) (37.5) (45.5) (0.0)

240/1257 59/336 32/187 25/165 16/72 11/64 8/52

(19.1) (17.6) (17.1) (15.2) (22.2) (17.2) (15.4)

914/1132 232/281 134/162 88/106 51/64 47/53 41/49

(80.7) (82.6) (82.7) (83.0) (79.7) (88.7) (83.7)

103/125 45/55 21/25 52/59 5/8 6/11 3/3

(82.4) (81.8) (84.0) (88.1) (62.5) (54.5) (100)

1017/1132 277/336 155/187 140/165 56/72 53/64 44/52

(80.9) (82.4) (82.9) (84.8) (77.8) (82.8) (84.6)

(95% CI, 7.39-23.76; P <.0005). After stratifying by sex, the odds remained highly signicant for women with CU (OR, 19.88; 95% CI, 10.15-38.92; P <.0005). Although men with CU had more RA than men in the control group, this trend did not reach signicance (OR, 2.96; 95% CI, 0.89-9.83; P 5 .062). Most of the patients (82.9%) were given a diagnosis of RA within 10 years of the diagnosis of CU, with 3.9% receiving a diagnosis in the rst 6 months after the diagnosis of CU. Rheumatoid factor was significantly more prevalent in patients with CU compared with control subjects: 2.1% versus 0% in the women, respectively (P < .0005), and 1.2% versus 0.02% in the men, respectively (P < .0005). The odds of having type I diabetes mellitus was 7.703 in patients with CU (95% CI, 4.78-12.65; P < .0005) compared with that in control subjects. The odds for women with CU were 12.92 (95% CI, 6.53-25.53; P <.0005), and they were 2.34 for men (P 5 .015). Most patients were given a diagnosis of type I diabetes mellitus in the years after the diagnosis of CU (84.8%), and no patient was diagnosed within the rst 6 months after the diagnosis of CU. As shown in Table I, when comparing women with CU with women in the control group, the odds of having Sjgren o syndrome, celiac disease, and SLE were 23.30, 57.8, and 26.71, respectively (P < .0005). There was no signicant difference in the prevalence of these diseases among the men. As depicted in Table II and Fig 1, most of the patients with each of the abovementioned autoimmune diseases were given diagnoses during the 10 years after the diagnosis of CU was rst registered. For all autoimmune diseases, there was no peak in the number of patients receiving a diagnosis in the rst 6 months after the diagnosis of CU that could be attributed to the workup of CU. The odds of patients with CU having any additional autoimmune disease was 17.343 compared with that seen in the control group (95% CI, 14.222-21.148; P < .0005). Of the 1872 patients with CU with accompanying autoimmune diseases, 12.5% (n 5 1591) had 1 autoimmune disease, and 2.1% (n 5 263) had 2 diseases (hypothyroidism and another autoimmune disease, mostly

RA). Sixteen (0.1%) patients with CU had 3 additional autoimmune diseases. One patient had 4 accompanying autoimmune diseases, and 1 had 5 such diseases.

Serologic and laboratory markers and CU Some laboratory markers serve as additional indicators for the existence of autoimmune and inammatory processes. We looked for abnormal laboratory test results in relation to the diagnosis of CU. Table III summarizes the abnormal test results. The MPV value, an indicator of inammation, was abnormally high in 28.5% (n 5 3662) of the patients with CU compared with 1.2% (n 5 129) of control subjects (P < .0005). This difference persisted when we separated the groups by sex. Antithyroid peroxidase antibodies, antithyroglobulin antibodies, and rheumatoid factor showed the same trends and are detailed above. Antinuclear antibodies were signicantly more prevalent in women (2.5%) and men (0.9%) with CU than in women (0.1%) and men (0.2%) in the control group (P < .0005). The other serologic markers were abnormal in small numbers of patients with CU and control subjects, as presented in Table III.

DISCUSSION This study is the rst to conrm the association between CU and the main autoimmune diseases and serologic markers in a very large population. These observations have important diagnostic, therapeutic, and prognostic implications. The present study, which is one of the largest studies ever conducted on CU, indicates that women were affected twice as often as men, which is in agreement with previous reports in the literature.10,11 This sex difference is also in line with those reported for other autoimmune diseases. Thyroid diseases were the most common autoimmune diseases accompanying patients with CU. Hypothyroidism and

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FIG 1. Time of diagnosis of autoimmune diseases in relation to the point of diagnosis of CU.

hyperthyroidism were found in 10% and 2.6% of patients with CU, respectively, and were signicantly more common than in the control group and signicantly more prevalent than the 2.2% and 0.5% reported in the general population.12 Because the

association between CU and thyroid autoimmune diseases was rst described many years ago in the pioneering work of Leznoff and Sussman,3 several studies have addressed the question of whether these 2 disorders are associated.6 However, they differ

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TABLE III. Abnormal serologic markers presented as total numbers and percentages of total tests performed
Marker Female patients Female control Male patients Male control Total patients Total control with CU (%)* subjects (%)* P value with CU (%)* subjects (%)* P value with CU subjects

MPV Antithyroid peroxidase antibodies Antinuclear antibodies Rheumatoid factor Antithyroglobulin antibodies Antitransglutaminase IgA antibodies Antiparietal cell antibodies Antidouble-stranded DNA antibodies Anticardiolipin antibodies

2652 508 208 180 117 26 23 15 14

(31.3) (6) (2.5) (2.1) (1.4) (0.3) (0.3) (0.2) (0.2)

15 (1) 5 (0.3) 1 (0.1) 0 1 (0.1) 0 0 0 0

<.0005 <.0005 <.0005 <.0005 <.0005 .03 .04 .10 .11

1010 90 40 53 21 5 7 1

(23.5) (2.1) (0.9) (1.2) (0.5) (0.1) (0.2) (0.02) 0

114 49 16 2 4 3 2 1 2

(1.2) (0.5) (0.2) (0.02) (0.04) (0.03) (0.02) (0.01) (0.02)

<.0005 <.0005 <.0005 <.0005 <.0005 .06 .00 .58 .33

3662 598 248 233 138 31 30 16 14

129 54 17 2 5 3 2 1 2

*Percentage represents positive results of total number of tests performed.

in design, the size of the studied populations is not large, and some lack a control group.13-17 In most of these reports, thyroid disorder was dened as having high titers of antithyroid antibodies. Whether these antibodies predispose to autoimmune thyroiditis and hypothyroidism is not clear. In our study antithyroid peroxidase antibodies and antithyroglobulin antibodies were signicantly more prevalent in the CU group than in the control group and were accompanied by a physicians diagnosis of thyroid disease. This is the rst large controlled study demonstrating a correlation between clinical thyroid diseases, serologic markers of thyroid autoimmunity, and CU. The mechanism of these associations is not known. Aversano et al18 hypothesized that the inammatory status inicted by thyroid-stimulating hormone led to ares of urticaria, as well as to the production of antithyroid antibodies. We can soundly demonstrate that these disorders are associated, but although suspected, a common pathogenesis cannot be proved. The association between CU and thyroid disease might be due to a shared susceptibility to autoimmune or chronic inammatory processes. This hypothesis is supported by the additional nding that all other autoimmune diseases we investigated were more common in patients with CU. RA was the second most common autoimmune disease in patients with CU. It was found in 1.9% of female patients with CU, which is signicantly more prevalent than in the control group and the prevalence of 0.5% to 1.1% of RA reported in the general population.19 Rheumatoid factor was positive signicantly more often in women and men with CU compared with control subjects. Type I diabetes mellitus, Sjgren syndrome, celiac disease, and o SLE were each signicantly more prevalent in women with CU than in control women. The prevalence of Sjgren syndrome and o SLE was signicantly higher than reported in the literature (3.9/ 105-0.1% and 2-4.7/105, respectively).20,21 This was accompanied by signicantly more patients with CU with positive antinuclear antibody results. The high prevalence of these autoimmune diseases in patients with CU adds more strength to the assumption that CU is also a member of this group of diseases. When autoimmune diseases overlap, the second or third disease often appears while the rst one is still active, even if the patient is receiving immunosuppressive treatment. In accordance with this, the data we present show that few autoimmune diseases were diagnosed during the rst 6 months after the diagnosis of CU, but most have been continuously revealed over a period of more than 10 years. There was no peak in the number of patients receiving diagnoses in the rst 6 months after the diagnosis of CU. This suggests that the

accompanying autoimmune diseases were independently diagnosed and not as part of the CU workup. Our data do not include the timeframe of the appearance of the different autoantibodies in relation to the diagnosis of CU. It is well known that in patients with SLE, as well as in those with RA and Hashimoto thyroiditis, the appearance of autoantibodies precedes the clinical manifestation by many years, sometimes more than a decade. If CU truly facilitates the clinical appearance of other autoimmune phenomena, then it is possible that autoantibodies, either those related to CU or to other diseases, appear some time along the course of the disease. This might have driven the chain of events further, and after a time lag from the autoantibody production, the other clinical autoimmune disease presented itself. Overlapping autoimmune diseases tend to relate between them in clinical signs and symptoms and probably also in physiopathologic mechanisms. Genetic factors might explain these common origins.22 MHC complex genes have been associated with rheumatic autoimmune diseases, as well as polymorphisms of IL10, IFNG, and TNFA. For example, Eyre et al23 reported recently that variation within the TAGAP gene at 6q25.3 is associated with 3 autoimmune diseases: RA, type I diabetes mellitus, and celiac disease. As considerably more genetic data exist regarding overlap between many autoimmune diseases and according to the data we present here, ndings of similar links regarding CU might be expected in the future. Although autoantibodies probably represent an important pathogenic mechanism in some patients with CU, it might not be the only one. The activation of the coagulation system in patients with CU has gained attention in the last few years. Scattered reports propose an additional explanation for the pathophysiology of CU. A recent study evaluated patients with CU by using an autologous plasma skin test instead of the autologous serum skin test (ASST).24 This study showed that patients with CU more commonly have a positive autologous plasma skin test result (86%) than a positive ASST result (53%). It also showed that levels of prothrombin fragment 112, a marker of thrombin generation, were signicantly increased in patients compared with those seen in control subjects. Because autoantibodies are equally present in serum and plasma, this nding suggested a possible role of clotting factors in the wheal-and-are reactions induced by autologous plasma. The hypothesis proposed to explain this difference is that factors in the plasma (not serum) might play a role in the skin reaction and promote the urticaria itself. This activation of the extrinsic coagulation pathway resulting in thrombin

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generation might be platelet derived. Being aware of these preliminary data and possible mechanisms, we evaluated the relation between CU and MPV. Surprisingly, high platelet volume was the most common abnormal laboratory nding in patients with CU. In our group 3552 of the patients with CU had increased MPV values, 31% of the women and 23% of the men, which was signicantly more than in the men and women of the control group. Preliminary data supporting our ndings were published recently by Magen et al.25 In their report 171 patients with CIU were studied, and a subgroup comprised of 45% of the patients with positive ASST results had signicantly increased MPV values. MPV is the most commonly used measure of platelet size and is a potential marker of platelet reactivity. Larger platelets are metabolically and enzymatically more active. Platelets secrete and express a large number of substances that are crucial mediators of coagulation, inammation, thrombosis, and atherosclerosis.26,27 Several studies report a correlation between higher MPV values and active inammatory disease.28,29 For example, small studies conducted on patients with RA have demonstrated a correlation between increased MPV values and increased disease activity and inammatory markers.28,30 Similar data published regarding high MPV values observed in patients with newly diagnosed celiac disease might be a reection of the ongoing intestinal inammation. MPV values were normalized with the introduction of a gluten-free diet, which might indicate resolution of intestinal inammation.31 We propose evidence that suggests a role for platelets in the pathogenesis of CU. Large activated platelets might have inuence on histamine-releasing effector cells, probably through activation of the coagulation cascade. Thus we suggest that at least some patients with CU represent a phenotype within the spectrum of immune-mediated inammatory diseases. The current study has strengths and limitations. We assembled a large population of patients with CU and compared them with a large matching control group. Although CU is a clinical diagnosis, it was dened by allergy or dermatology specialists experienced in this disease. The study looked into the correlation between CU and a panel of autoimmune conditions and serologic markers and was found to be signicant for most of them. Consequently, although this is a retrospective study, the presented data give considerable strength to the concept that CU is part of the family of autoimmune diseases. They also add substantial information on the role of autoantibodies and proinammatory markers in patients with CU. This study is subject to the limitations inherent in any large population survey. To evaluate whether and which autoimmune diseases and serologic markers have the most important effect or relation to CU would require detailed information regarding the course of disease and close follow-up, which are impossible in studies of this extent. Identifying the pathogenic mechanism or mechanisms for CU might lead to new targets of interventions beyond the current mainstay of often inadequate symptomatic treatment directed against histamine receptors. This work provides a framework for future understanding the disease process that might help the development of individualized therapies and increase awareness of comorbidities, as well as help in the prediction of disease prognosis.
We thank Nava Jelin for her excellent help in statistical analyses.

Clinical implications: CU is probably one of the autoimmune diseases. Understanding the disease process might help the development of individualized therapies and increase awareness of comorbidities, as well as help in the prediction of disease prognosis.
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ALLERGY ARCHIVES LYSOZYME AND FLEMING In 1922 Fleming described a substance that dissolves certain bacteria and I have called it lysozyme.1 The test organism was a harmless bacteria obtained in nasal secretion which he named Micrococcus lysodeikticus. Material is rich in lysozyme in tears, nasal mucus, sputum, cartilage, skin and to a very marked degree in hen egg white. Fleming when lecturing to medical students made them clip their nails and even those clippings showed lysozyme activity. Dropping lemon juice into the eye was an unpleasant procedure, producing tears which were difficult to collect. In a dilution of 1 in 243,000, they have a marked bactericidal effect.2 Human tears even in a dilution of 1 in 2,000,000 still show lytic activity to the test organism but dried egg white in dilution of 1 in 80,000,000 showed bacterolysis. Hen egg yolk is relatively inactive and indeed it inhibits the lysozyme activity of egg white. Lysozyme is present in human milk (and in cows milk). In the breastfed infant, lysozyme is found in feces by the fourth day. Fleming when teaching medical students in mid 1930 stressed that he was more hopeful that lysozyme rather than the substance from the mold penicillium which he designated penicillin, might one day be used therapeutically in clinical medicines. In a lecture given in 1973,3 identical twin boys aged 7 with eczema, rhinitis, and asthma were described. One was acutely allergic to egg white and yolk while the other one reacted to egg white while egg yolk caused no clinical problems. During question time Prausnitz-Giles asked whether lysozyme had been tested for as he thought this was the possible explanation of the different responses. Clinical allergic reactions may occur in children at the first egg ingestion.4 It has been shown by Walsh5 that there are 4 distinct groups of hen egg allergens binding IgE to the sera of egg allergic children and IgE antibodies against Gal d 4 (lysozyme) must always be a possible allergen. It was hoped that lysozyme might be mass produced as a curative product for AIDS.6 Some countries do produce lysozyme commercially. From Italy comes the account of a 20-month-old eczematous child who had never eaten egg but who on using a nasal decongestant which contained lysozyme, developed rhinitis and asthma within a few minutes.7 Fleming, when penicillin became freely available, would not accept that it could cause allergic reactions, he thought that untoward reactions were due to impurities present.8 He would be delighted to know that lysozyme has been produced as a commercially available antibiotic but he would be disappointed to know that it too can cause allergic reactions. A. W. Frankland, MD
1. Fleming A. On a remarkable bacteriolytic element found in tissues and secretions. Proc Roy Soc Med 1922; Series B, 93:306-17. 2. Fleming A. Lysozyme. Proc Roy Soc Med 1932;26:71-84. 3. Frankland AW. Allergy: immunity gone wrong. Proc Roy Soc Med 1973;66:365-8. 4. De Boissieu D, DuPont C. Natural course of sensitization to a hens egg in children not previously exposed to egg ingestion. Allerg Immunol (Paris) 2006;38:113-7. 5. Walsh BJ, Hill DJ, Macoun P, Cairns D, Howden MEH. Detection of four distinct groups of hen egg allergens binding IgE in the sera of children with egg allergy. Allergol Immunopathol (Madr) 2005;33:183-91. 6. Tsuchiya Y, Morioka K, Shiraj J, Yoshida K. Establishment of a mass production system for human lysozyme as a curative medicine to AIDS. Int Conf AIDS 2004;15:abs no. WePeA5628. 7. Artesani MC, Calzone L, DUrbano L, Donnanno S, Cavagni G. Egg sensitization caused by immediate hypersensitivity reaction to drug containing lysozyme. Ann Allerg, Asthma & Immunol 2008:101-5. 8. Frankland AW. Penicillin sensitivity. In Fleming A, Penicillin. Its practical application. London: Butterworth, 1950; pp 425-31.